Composition and methods for treating nematode infections

ABSTRACT

1. AN ORALLY INGESTIBLE NEMATODE INFECTION TREATMENT COMPOSITION FOR MAMMALS WHICH COMPRISES A THERAPEUTICALLY ACCEPTABLE SOLID CARRIER AND AN EFFECTIVE NON-TOXIC NEMATODE INFECTION TREATMENT AMOUNT OF A SALT OF THE FORMULA   2-((1-R,2,5-DI(H3C-)-PYRROL-3-YL)-CH=CH-),3-(H3C-),4-Z-   THIAZOLIUM X(-)   WHERE R IS SELECTED FROM THE CLASS CONSISTING OF ALKYL HAVING 1 TO 6 CARBON ATOMS, AND PHENYL OPTIONALLY SUBSTITUTED BY ONE OR MORE HALOGEN ATOMS, ALKYL GROUPS HAVING 1 TO 4 CARBON TOMS OR ALKOXY GROUPS HAVING 1 TO 4 CARBON ATOMS; Z IS SELECTED FROM THE CLASS CONSISTING OF PHENYL, P-HALOPHENYL, P-ALKOXYPHENYL WHERE THE ALKOXY HAS 1 TO 6 CARBON ATOMS, BIPHENYL, P-ALKOXYBIPHENYLYL WHERE THE ALKOXY HAS 1 TO 6 CARBON ATOMS, AND NAPHTHYL; AND X-IS THE ANION OF A PHARMACEUTICALLY ACCEPTABLE ACID.

United States Patent 3,851,060 COMPOSITION AND METHODS FOR TREATING NEMATODE INFECTIONS Robert Beck Burrows, Ardsley, and Arthur Page Phillips, Tuckahoe, N.Y., assignors to Burroughs Wellcome Co. No Drawing. Original application Mar. 2, 1970, Ser. No. 15,944, now abandoned. Divided and this application Jan. 6, 1972, Ser. No. 215,926 Claims priority, application Great Britain, Mar. 7, 1969, 12,158/69 Int. Cl. A61k 27/00 US. Cl. 424-270 32 Claims ABSTRACT OF THE DISCLOSURE 'Pyrrylvinylthiazolium salts of the following formula (I) N H30] Toni CIJHQ X (I) wherein R is an alkyl or an optionally substituted phenyl group; Z is phenyl, p-halophenyl, p-alkoxyphenyl, biphenylyl, p-alkoxybiphenylyl or naphthyl; and X is the anion of a pharmaceutically acceptable acid.

The compounds are useful in having activity against parasitic nematodes infecting warm-blooded animals.

This is a division of application Ser. No. 15,944, filed on Mar. 2, 1970, now abandoned.

This invention relates to quaternary ammonium salts, their synthesis, pharmaceutical compositions containing them, and their use as therapeutic agents.

The present invention provides compounds of formula wherein R is alkyl or is an optionally substituted phenyl group; Z is phenyl, p-halophenyl, p-alkoxyphenyl, biphenylyl, p-alkoxybiphenylyl or naphthyl; and X is the anion of a pharmaceutically acceptable acid.

The compounds of formula (I) have been found activeagainst parasitic nematodes, especially pinworms although the compounds also have activity against other nematodes such as whipworms, hookworms, etc. Thus they have been found active against Syphacia obvelata in mice, a screening organism for the human pinworm, Enterobius vermicularis, both organisms having similar lifecycles. Also, they have activity against Aspiculuris tetraptera in mice.

Most important, the compounds have high LD doses which, together with their good anthelmintic activities at low doses, gives them a high therapeutic index.

The compounds in which Z is biphenylyl are particularly preferred Other preferred compounds are those in which Z is p-alkoxyphenyl, the alkoxy having 1 to 6 carbon atoms, that is methoxy to hexoxy. When R is an alkyl group, it has 1 to 6 carbon atoms, that is methyl to hexyl. When R is a phenyl group, it may be substituted by one or more groups such as halogen (that is, chlorine, bromine,

3,851,060 Patented Nov. 26, 1974 fluorine and iodine); alkyl having 1 to 4 carbon atoms (methyl to butyl); or alkoxy having 1 to 4 carbon atoms (methoxy to butoxy). When Z is p-alkoxybiphenylyl, the alkoxy has 1 to 6 carbon atoms (methoxy to hexoxy).

Examples of particularly valuable compounds of formula (I) are:

2- [6- 1-n-butyl-2,5-dimethy1-3-pyrryl) vinyl] -4- (p-bromophenyl)thiaz0le methiodide;

2- ,B-( l-n-butyl-2,5-dimethyl-3-pyrryl vinyl] -4- (pmethoXyphenyDthiazole methiodide;

2- ,6- 1-n-butyl-2,5-dimethyl-3-pyrryl) vinyl] -4 (p-chlorophenyl)thiaz0le methiodide;

2- [B- 1-n-butyl-2,5-dimethyl-3-pyrryl) vinyl] -4- phenylthiazole methiodide;

2- 8- l-n-amyl-Z,S-dimethyl-S-pyrryl) vinyl] -4- phenylthiazole methiodide;

2 fll-n-amyl-Z,5-dimethyl-3-pyrryl) vinyl] -4- (p-chlorophenyl)thiaz0le methiodide;

2- [5- 1-phenyl-2,5-dimethyl-3 -pyrryl) vinyl] -4- (p-bromophenyl) thiazole methiodide;

2- [fil-n-amyl2,S-dimethyl-S-pyrryl) vinyl] -4- (p bromophenyl)thiaz0le methiodide;

2- [fi-( 1,2,5-trimethyl-3-pyrryl vinyl] -4- (p-bromophenyl)thiaz0le methiodide;

2- fi- 1,2,5 -trimethyl-3-pyrryl vinyl] -4- p-chlorophenyl)thiaz0le methiodide;

2- [B- 1,2,5-trimethyl-3 -pyrryl) vinyl] -4-,8-naphthylthiazole methiodide;

2- [5% 1,2,5 -trimethyl3-pyrryl) vinyl] -4-p-biphenylylthiazole methiodide;

2- [[i- 1-p-chlorophenyl-2,5-dimethyl-3-pyrryl)vinyl]-4-pbiphenylylthiazole methiodide;

2- [l l-phenyl-2,5-dimethyl-3-pyrryl) vinyl]-4- p-biphenylylthiazole methiodide;

2- 5-( l-ethyl-2,5-dimethyl-3 -pyrryll vinyl] -4- p-biphenylylthiazole methiodide;

2- [B-( 1-phenyl-2,5-dimethyl-3-pyrryl) vinyl] -4- phenylthiazole methiodide;

2- fil-ethyl-2,5-dimethyl-3 -pyrryl) -vinyl] 4'- phenylthiazole methiodide; and

2- [fi- 1 ,2,5-trirnethyl-3-pyrryl vinyl] -4-phenylthiazole methiodide.

Unless otherwise indicated, references in the specification and claims to pyrrylvinylthiazolinm salts of formula (I) mean salts of a pharmaceutically acceptable acid.

The compounds of formula (I) may be made by any method known for preparing compounds of an analogous chemical structure. Thus, they may be prepared by the reaction of a thiazolium compound of the formula (II) wherein Z, R and X are as defined above. The reaction is preferably carried out in the presence of a basic catalyst such as piperidine, but other bases of comparable or greater basic strength may be used, for example, amines (pyrrolidine, N-methylpyrrolidine) or an alkali metal hydroxide or an alkoxide. The reaction is conveniently carried out in the presence of a liquid medium which is, or contains, a polar liquid, in which the reactants may be dissolved or suspended in a finely divided form. The liquid medium for the reaction is preferably a lower alcohol (optionally containing water) such as methanol or ethanol, or' may be some other polar medium not reactive to the reactants such as dimethyl sulphoxide or sulfolane. The reaction is preferably conducted at a temperature from C. to the boiling point of the reaction mixture.

The intermediate 2,3-dimethy1-4-Z-thiazoliurn salts of formula (II) may be prepared by the following sequence of reactions, the last step providing for the quaternisation of the 2-methyl-4 Z-thiazole of formula (VI) by a methyl derivative CH A:

'where the symbol Z has the meanings given above, and A is a nucleophilic group or atom, for example, chlorine, bromine or iodine, or a methosulphate or p-toluenesulphonate group.

The compounds of formula (I) may also be prepared by the reaction of a phenacyl derivative of formula (VII) with a thioamide of formula (VIII) R ZCO.CH2A. CCH=CH\/ CHaHN CH3 (VII) (VIII) wherein Z, R and A are as defined above. This reaction proceeds via an intermediate thioimidate of formula (IX) ona S CH1 z-bo from wherein Z and R are as defined above, and this thioimidate itself, if desired, may be isolated and then converted to a compound of formula (I) as described below. The compounds of formula (I) are formed by the reaction of the phenacyl derivative of formula (VII) and the thioamide of formula (VIII) under conditions which convert the thioimidate intermediate (IX) to a compound of formula (I). In general, heating the reactants, or reacting them in the presence of an acid, will tend to form the compounds of formula (I). A temperature of 80 to 150 C. is conveniently employed to effect a rapid conversion to the compounds of formula (I). The acid may be a mineral acid such as hydrochloric or hydrobromic acid and preferably corresponds to the nucleophilic group or atom A which provides the anion X- of formula (I). The reaction is preferably performed in the presence of a polar liquid medium, for example, a lower alkanol such as ethanol or butanol, or a water/butanol mixture. The opti mum reaction conditions for forming the compounds of formula (I) vary according to the nature of the thioimidate intermediate, the group A and the liquid medium employed.

The thioimidates of formula (IX) and their acid addition salts may themselves be converted to the compounds of formula (I) by treatment with an acid, preferably a mineral acid, for example, hydrochloric or hydrobromic acid, which should preferably correspond to the thioim-idate salt, if used, and to the desired thiazolium salt of formula (I). The acid addition salts of the thioimidates of formula (IX) may also be converted to the compounds of formula (I) by heating the salts, preferably the hydrochloric or hydrobromic acid addition salts. The reaction is preferably conducted in a polar liquid medium, for example, a lower alkanol such as butanol, conveniently at a temperature of to 150 C.

The activity against nematodes of the compounds of for mula (I) resides in the cation, and the nature of the anion X is unimportant providing that the salt is pharmaceutically acceptable. Examples of suitable salts are the halides, sulphonates, sulphates and alkyl sulphates. The iodide, methosulphate and p-toluenesulphonate salts are preferred since they can be conveniently introduced in the quaternisation step by the use of methyl iodide, dimethylsulphate and methyl p-toluenesulphonate. The bromide salts may be prepared by the use of methyl bromide. Other salts may be prepared by conventional procedures, for example, by replacing the anion by double decomposition of either the 2,3-dimethyl-4-Z-thiazolium salt or the 2-(R-2,5-dimethyl-3-pyrryl)-3 methyl-4-Z-thiazolium salt. For example, the chloride salts may be prepared from the iodide salts by shaking the latter with silver chloride in alkanolic solution; and the chloride and bromide salts may be converted to the iodide salts by reaction with potassium iodide, either before or after their isolation from the reaction mixture.

For the treatment of nematode infections in warmblooded animals, the compounds of formula (I) are conveniently administered in pharmaceutical compositions comprising the compounds and an acceptable carrier therefor. Any well known type of pharmaceutical composition may be used for this purpose, but compositions for oral use are preferred. For administration of the compounds of formula (I) in dry solid form, they may be presented as capsules, granules, pills, powders, tablets, boluses, or in a gelatin cube, containing the desired amount of the compound distributed in such carriers as are usually employed. The compositions are prepared in general by intimately and uniformly mixing the active ingredient with the carrier which may comprise one or more diluents, fillers, disintegrating agents and binders. Boluses and tablets may be compounded by techniques well known in the art, for example, by compression on a tabletting machine. The tablets may be formed so as to disintegrate rapidly, or to provide a prolonged or delayed action, or to provide a predetermined release of the active ingredient at successive intervals. The tablets also may be coated. Capsules are readily prepared by combining the active ingredient with any desired excipient and filling into the capsule.

The compounds of formula (I) may also be administered in a liquid preparation or as a component of the feed of the animal. Liquid preparations may comprise a suspension or solution of the active ingredient in water or in a vegetable or mineral oil or an emulsion thereof. The liquid carrier itself may consist of one or more ingredients, for example, liquid diluents, buffers, bacteriostats, sweeteners, colouring matter, dispersing agents, suspending agents and emulsifiers.

The normal unit dose range for the compounds of formula (I) is from 5 to mg. cation/kg. body weight of the animal being treated. The preferred unit dose range is 5 to 25 mg./kg.

The invention thus also provides a method for the preparation of the compounds of formula (I) as hereinbefore described.

The invention therefore further provides a method for the treatment of a nematode infection in warm-blooded animals or mammals (for example dogs, cats and humans) comprising the administration (preferably oral) of an effective amount of a compound of formula (I) to the host of the infection. It also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier therefor, and a method of preparing such a composition by admixture of the components.

The invention also provides a pharmaceutical composition for use as an anthelmintic which comprises essentially an effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier therefor.

The following examples illustrate the invention. All temperatures are in degrees Celsius.

EXAMPLE 1 2-{18-(1-phenyl-2,5-dimethyl-3-pyrryl)vinyl}-4-(p-biphenylyl) thiazole methiodide p-Phenylphenacyl bromide (27.5 g., 0.1M) and thioacetamide g., 0.133M) were mixed and heated in methanol (150 ml.). The reaction mixture developed a strong acidic reaction almost at once. After heating at 100 for 12 hours, a part of the methanol was evaporated and water and ammonia were added, thus precipitating the thiazole base. This Was collected and purified by recrystallisation from methanol and gave colourless crystals of 2-methyl-4-p-biphenylyl thiazole (23 g., 90- 95% yield) melting at 120121 C.

A solution of 2-methyl-4-p-biphenylyl thiazole (25 g., 0.1M) and methyl iodide (22 g.) in dimethylformamide (70 ml.) was heated for 6-8 hours at 100 C. Upon addition of excess ether and cooling, there was obtained 2- methyl-4-(p biphenylyl)thiazole methiodide (3032 g., 75-80% After purification by digesting with hot methanol, this compound had a melting point of 272-273" C.

To a mixture of 2-methyl-4(p biphenylyl)thiazole methiode (7.9 g., 0.02M) and l-phenyl-Z,S-dimethylpyrrole-3-carboxaldehyde (4.8 g., 0.024M) in methanol (60 cc.) was added piperidine (2 cc.). The reaction mixture was heated on a steam bath for 3 hours. An orange condensation product was formed within a few minutes. The longer heating period was employed because of the relative insolubility of both the starting compound (thiazole methiodide) and the product, in order to ensure nearly complete transformation of this insoluble reactant into the insoluble product.

After filtration and washing with methanol and ether, 2 {B (1-phenyl-2,5 dimethyl-3-pyrryl)vinyl}-4-(p-biphenyly1)thiazole methiodide was obtained. After further digestions with hot methanol an orange product melting at 2l6-218 C. was obtained.

1-phenyl-2,S-dimethylpyrrole 3 carboxaldehyde was prepared as follows. Aniline (19 g., 0.2M), acetonylacetone (23 g., 0.2M) and glacial acetic acid (2 cc.) were mixed and heated for a half to one hour on a steam bath. Upon cooling white crystals formed which were recrystallised from ethanol to give 2,5-dimethyl-l-phenylpyrrole (31 to 33 g., 95%+ yield) melting at 51 to 52 C.

To dimethylformamide (32 cc., 0.4M:L-) chilled in an ice bath, phosphorus oxychloride (15.3 g., 0.1M) (9 cc.) was gradually added. To this cooled mixture, 2,5-dimethyll-phenylpyrrole (17 g., 0.1M) was added carefully and the reaction mixture was removed from the ice bath and was heated for 2 hours at 100 C. (steam bath). The mixture was then poured on to one hundred to two hundred grams of ice. The aqueous ice mixture was basified to pH 11 with 50% aqueous sodium hydroxide and gave white crystals of the aldehyde product. This was collected and recrystallised from ethanol giving 18 grams (90%) yield of purified aldehyde, melting point 9091 C.

EXAMPLE 2 By the method of Example 1 the following compounds were prepared.

Z-{fll-n-butyl-2,5-dimethyl-3-pyrryl vinyl}-4- (p-bromophenyl)thiazole methiodide, m.p. 181182 C.;

2- fl-( 1-n-butyl-2,5-dimethyl-3-pyrryl) vinyl}-4- (p-methoxyp'henyl)thiazole methiodide, m.p. 148149 C.;

2-{ 8-1-n-buty1-2,S-dimethyl-3-pyrryl)vinyl}-4- (p-chlorophenyl)thiazole methiodide, m.p. l69170 C.;

2-{13- l-n-'butyl-2,5-dimethyl-3-pyrryl vinyl}-4-phenylthiazole methiodide, m.p. 182183 C.;

2-{fl- 1-n-amyl-2,S-dimethyI-S-pyrryl vinyl}-4-phenylthiazole methiodide, m.p. 108-109 C.;

2-{fi- (1-n-amyl-2,5-dimethyl-3-pyrryl) vinyl}-4-(p-chlorophenyl)thiazole methiodide, m.p. 181182 C.;

2-{5 (1-phenyl-2,S-dimethyl-3-pyrryl)vinyl}-4- (pbromophenyl) thiazole methiodi-de (monohydrate) m.p. 222-223" C.;

2-{13- l-n-amyl-2,5-dimethyl-3 -pyrryl) vinyl}-4- (p-brornophenyl)thiazole methiodide (hemihydrate), m.p. 175- 176 C.;

2-{ ,B-( 1,2, 5-trimethyl-3-pyrryl) vinyl}-4- p-bromophenyl) thiazole methiodide, m.p. 228-229 C.;

2-{3-(1,2,5-trimethyl-3-pyrryl)vinyl}-4-(p-chlorophenyl) thiazole methiodide, m.p. 229230 C.;

2- {[i- 1,2,S-trimethyl-B-pyrryl) vinyl}-4-,B-naphthylthiazole methiodide, m.p. 22l-222 C.;

2-{;8-( 1,2,5 -trimethyl-3 -pyrryl) vinyl}-4-p-biphenylylthiazole methiodide (hemihydrate), m.p. 222-223 C.;

2{,8- (1-p-chlorophenyl-2,5-dimethyl-3-pyrryl)vinyl}-4-pbiphenylylthiazole methiodide, m.p. 227228 C.;

2-{ 3- l-ethyl-2,5-dimethyl-3-pyrryl) vinyl}-4-p-biphenylylthiazole methiodide (hydrate), m.p. 192193 C.;

2-{18- 1-phenyl-2,5-dimethyl-3-pyrryl) vinyl}-4-phenylthiazole methiodide, m.p. 223224 C.;

2- {fl- 1-ethyl-2,5din1ethyl-3-pyrryl) vinyl}-4-phenylthiazole methiodide, m.p. 2082l0 C.;

2-{13- 1,2,5-trimethyl-3 -pyrryl vinyl}-4-phenylthiazole methiodide, m.p. 228-230 C.

EXAMPLE 3 2- B-( 1-phenyl-2,5-dirnethyl-3-pyrryl vinyl}-3methyl- 4-p-biphenylylthiazolium bromide A solution of chloroacetmethylamide (Jacobs and Heidelberger, J. Biol. Chem, 1915, 21, (53.75 g.) and triphenylphosphine (144 g.) in benzene (125 ml.) was heated in a bath at 100 for 24 hours. The solid was collected and washed with benzene. This N-methylcarbamoylmethyl-triphenylphosphonium chloride had m.p. 252 (elferv) To a stirred ice-cold solution of this phosphonium salt (18.5 g.) and 2,S-dimethyl-l-phenylpyrrole-3-aldehyde (9.95 g.) in methanol (100 ml.) was added slowly a solution of sodium methoxide prepared by dissolving sodium (1.25 g.) in methanol (50 ml.). The mixture was stirred for a further 1 hour at room temperature, water was added and most of the methanol was evaporated. The residual mixture was extracted with ether, and the ether extract was washed with water, dried and evaporated. The residue was dissolved in methanol and allowed to crystallise. The resulting 3-(2,5-dimethyl-l-phenylpyrrol- 3-yl)acrylomethylamide formed colourless prisms of a hydrate (m.p. 8590) which on drying gave the anhydrous amide, m.p. 157-158.

The foregoing amide (6.4 g.) was dissolved in pyridine (50 ml.), phosphorus pentasulphide (3 g.) was added and the mixture was refluxed with mechanical stirring for 30 minutes. The mixture was poured into water and the insoluble oil was extracted with chloroform, and the extract was dried and evaporated. The residue was purified by chromatography on alumina in chloroform solution togive 3-(2,5-dimethyl-l-phenylpyrrol-S-yl)acrylothiomethylamide as a yellow glassy material.

A solution of the thioamide (2 g.) and p-phenylphenacyl bromide (2.05 g.) in acetone (20 ml.) was refluxed for 2 hours. The bright yellow solid which had come out of solution was collected. This p-p'henylphenacyl-N-methyl-3-(2,5dimethyl-l-phenylpyrrol 3 yl)acrylothioimidate hydrobromide had m.p. (efferv.), unchanged by recrystallisation from ethanolether.

The above thioimidate hydrobromide (1 g.) was heated on the steam-bath with hydrobromic acid (5 ml. of 47%) for 25 minutes. The cooled mixture was diluted with water and neutralised by addition of sodium hydroxide solution. The solid was collected and recrystallised from ethanol to give light brown prisms, m.p. 202 (etferv.), of 2-{fi- 7 (l-phenyl 2,5 dimethyl-3-pyrryl)vinyl}-3-methyl-4-pbiphenylylthiazolium bromide.

Treatment of a methanolic solution of the bromide with aqueous potassium iodide gave the corresponding iodide, m.p. 216 (decomp.).

EXAMPLE 4 2-{fl-(1,2,5-trimethyl-3-pyrryl)vinyl}-3-methyl-4pbromophenylthiazolium bromide under reflux. The yellow solid which soon came out of solution was collected after 1 hour, and recrystallised from methanol to give deep yellow prisms, m.p. 180 (decomp.), of p-bromophenacyl-N-methyl-3-(1,2,5-trimethylpyrrol-3-yl)acrylothioimidate hydrobromide.

This thioimidate hydrobromide (1 g.) in methanol ml.) and hydrobromic acid (2.5 ml. of 47%) was boiled for 15 minutes. On cooling, the solution deposited deep yellow prisms, m.p. 216 (decomp.), of 2-{B-(l,2,5-trimethyl-3-pyrryl)viny1}-3-methyl-4-p-bromophenyl thiazolium bromide.

The corresponding iodide, prepared from the bromide using potassium iodide solution, had m.p. 228 (decomp.).

(b) A solution of 3-(1,2,5-trimet-hylpyrrol-3-yl)acrylothiomethylamide (1.04 g.) and p-bromophenacyl bromide (1.4 g.) in ethanol ml.) containing hydrobromic acid (0.5 ml. of 47 was refluxed for 1 /1 hours. The dark solution was cooled, and the crystals were collected and recrystallised from methanol to give deep yellow prisms, m.p. 216 (decomp.), of 2-{,8-(l,2,5 trimethyl-3-pyrryl)vinyl} 3 methyl 4 p-bromophenyl thiazolium bromide.

EXAMPLE 5 A tablet was made from the following ingredients:

(i) 2-{5-(1 phenyl 2,5 dimethyl-3-pyrry1)vinyl}- 4 p biphenylylthiazole methiodide (calculated as the base) 250 (ii) Lactose B.P. 100 (iii) Starch B.P. (iv) Gelatin 8 (v) Magnesium stearate B.P. 5

Ingredients (i), (ii) and half of (iii) were admixed and granulated with a solution of (iv) in 50% (v./v.) aqueous ethanol. The remainder of (iii) and the magnesium stearate (v) were added to the dried granules and the mixture compressed to form tablets.

50 mg. base/5 ml. (ii) Compound tragacanth powder B.P. g 4.0 (iii) Syrup B.P ml 20.0 (iv) Glycerin B.P. ml... 5.0 (v) Methyl hydroxybenzoate B.P g 0.1

(vi) Purified water B.P. to 100.0 ml.

A paste was prepared of (i) and (ii) using (iii) and (iv). Ingredient (v) was dissolved in the greater part of (vi), using heat, and the solution used to dilute the paste previously prepared. The volume of the resultant suspension was adjusted using the rest of the purified water.

What we claim is:

1. An orally ingestible nematode infection treatment composition for mammals which comprises a therapeutically acceptable solid carrier and an effective non-toxic nematode infection treatment amount of a salt of the formula zmqjaacnill kHz where R is selected from the class consisting of alkyl having 1 to 6 carbon atoms, and phenyl optionally substituted by one or more halogen atoms, alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms; Z is selected from the class consisting of phenyl, p-halophenyl, p-alkoxyphenyl where the alkoxy has 1 t0 6 carbon atoms, biphenylyl, p-alkoxybiphenylyl where the alkoxy has 1 to 6 carbon atoms, and naphthyl; and X- is the anion of a pharmaceutically acceptable acid.

2. A composition according to claim 1 wherein Z is selected from the class consisting of biphenylyl, p-alkoxybiphenylyl, and naphthyl.

3. A composition according to claim 1 wherein Z is selected from the class consisting of phenyl and p-alkoxyphenyl.

4. A composition according to claim 1 wherein Z is phalophenyl.

5. A composition according to claim 1 wherein Z is selected from the class consisting of biphenylyl and phalophenyl, and R is selected from the class consisting of alkyl and optionally substituted phenyl.

6. A composition according to claim 1 in which the salt is 2 [fi-(l-n-amyl 2,5 dimethyl 3 pyrryl)vinyl]- 3 methyl 4 p bromophenylthiazolium cation with the anion of a pharmaceutically acceptable acid.

7. A composition according to claim 1 in which the salt is 2 [;3-(l-ethyl 2,5 dimethyl 3 pyrryl)vinyl]- 3 methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

8. A composition according to claim 1 in which the salt is 2-[fl-(1-phenyl 2,5 dimethyl 3 pyrryl)vinyl]- 3 methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

9. A composition according to claim 1 in which the salt is 2-[p(1-p-chlorophenyl 2,5 dimethyl-3-pyrryl) vinyl] 3 methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

10. A composition according to claim 6 wherein the anion is iodide.

11. A composition according to claim 7 wherein the anion is iodide.

12. A composition according to claim 8 wherein the anion is iodide.

13. A composition according to claim 9 wherein the anion is iodide.

14. A method for the treatment of a nematode infection in a mammal which comprises orally administering to the nematode infected mammal an effective non-toxic nematode infection treatment dose of a salt of the formula J TCHHLI where R is selected from the class consisting of alkyl having 1 to 6 carbon atoms and phenyl optionally substituted by one or more halogen atoms, alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms; Z is selected from the class consisting of phenyl, phalophenyl, p-alkoxyphenyl where the alkoxy has 1 to 6 carbon atoms, biphenylyl, p-alkoxybiphenylyl where the alkoxy has 1 to 6 carbon atoms, and naphthyl; and X" is the anion of a pharmaceutically acceptable acid.

15. A method according to claim 14 wherein Z is selected from the class consisting of biphenylyl, p-alkoxybiphenylyl, and naphthyl.

16. A method according to claim 14 wherein Z is selected from the class consisting of phenyl and p-alkoxyphenyl.

17. A method according to claim 14 wherein Z is phalophenyl.

18. A method according to claim 14 wherein Z is selected from the class consisting of biphenylyl and p-halophenyl, and R is selected from the class consisting of alkyl and optionally substituted phenyl.

19. A method according to claim 14 in which the salt is 2-[6-(1-n-amyl 2,5 dimethyl 3 pyrryl)vinyl]-3- methyl 4 p bromophenylthiazolium cation with the anion of a pharmaceutically acceptable acid.

20. A method according to claim 14 in which the salt is Z-[fl-(l-ethyl 2,5 dimethyl 3 pyrryl)viny1]-3- methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

21. A method according to claim 14 in which the salt is Z-[B-(l-phenyl 2,5 dimethyl 3 pyrryl)vinyl]-3- methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

22. A method according to claim 14 in which the salt is Z-[fl-(l-p-chlorophenyl 2,5 dimethyl 3 pyrryl) vinyl] 3 methyl 4 p biphenylylthiazolium cation with the anion of a pharmaceutically acceptable acid.

23. A method according to claim 19 wherein the anion is iodide.

24. A method according to claim 20 in which the anion is iodide.

25. A method according to claim 21 in which the anion is iodide.

26. A method according to claim 22in which the anion is iodide.

27. A method according to claim 14 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight.

28. A method according to claim 15 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight.

29. A method according to claim 19 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight.

30. A method according to claim 10 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight.

31. A method according to claim 21 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight.

32. A method according to claim 22 in which the dose is 5 to 100 mg. cation/kg. of mammal body weight,

References Cited UNITED STATES PATENTS 2,639,282 5/1953 Sprague et al 260240 E JEROME D. GOLDBERG, Primary Examiner 

1. AN ORALLY INGESTIBLE NEMATODE INFECTION TREATMENT COMPOSITION FOR MAMMALS WHICH COMPRISES A THERAPEUTICALLY ACCEPTABLE SOLID CARRIER AND AN EFFECTIVE NON-TOXIC NEMATODE INFECTION TREATMENT AMOUNT OF A SALT OF THE FORMULA 